Browsing by Author "Liang, Yanping"
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- Casein Kinase 1 Epsilon Regulates Glioblastoma Cell SurvivalVarghese, Robin T.; Young, Sarah; Pham, Lily; Liang, Yanping; Pridham, Kevin J.; Guo, Sujuan; Murphy, Susan F.; Kelly, Deborah F.; Sheng, Zhi (Nature, 2018-09-11)Glioblastoma is the most common malignant brain cancer with a dismal prognosis. The difficulty in treating glioblastoma is largely attributed to the lack of effective therapeutic targets. In our previous work, we identified casein kinase 1 ε (CK1ε, also known as CSNK1E) as a potential survival factor in glioblastoma. However, how CK1ε controls cell survival remains elusive and whether targeting CK1ε is a possible treatment for glioblastoma requires further investigation. Here we report that CK1ε was expressed at the highest level among six CK1 isoforms in glioblastoma and enriched in high-grade glioma, but not glia cells. Depletion of CK1ε remarkably inhibited the growth of glioblastoma cells and suppressed self-renewal of glioblastoma stem cells, while having limited effect on astrocytes. CK1ε deprivation activated β-catenin and induced apoptosis, which was further counteracted by knockdown of β-catenin. The CK1ε inhibitor IC261, but not PF-4800567, activated β-catenin and blocked the growth of glioblastoma cells and glioblastoma stem cells. Congruently, IC261 elicited a robust growth inhibition of human glioblastoma xenografts in mice. Together, our results demonstrate that CK1ε regulates the survival of glioblastoma cells and glioblastoma stem cells through β-catenin signaling, underscoring the importance of targeting CK1ε as an effective treatment for glioblastoma.
- A cell–ECM mechanism for connecting the ipsilateral eye to the brainSu, Jianmin; Sabbagh, Ubadah; Liang, Yanping; Olejníková, Lucie; Dixon, Karen G.; Russell, Ashley L.; Chen, Jiang; Pan, Yuchin Albert; Triplett, Jason W.; Fox, Michael A. (National Academy of Sciences, 2021-10-15)Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.
- Molecular Analysis of BRCA1 in Human Breast Cancer Cells Under Oxidative StressGilmore, Brian L.; Liang, Yanping; Winton, Carly E.; Patel, Kaya; Karageorge, Vasilea; Varano, A. Cameron; Dearnaley, William J.; Sheng, Zhi; Kelly, Deborah F. (Nature Publishing Group, 2017-03-06)The precise manner in which physical changes to the breast cancer susceptibility protein (BRCA1) affect its role in DNA repair events remain unclear. Indeed, cancer cells harboring mutations in BRCA1 suffer from genomic instability and increased DNA lesions. Here, we used a combination of molecular imaging and biochemical tools to study the properties of the BRCA1 in human cancer cells. Our results reveal new information for the manner in which full-length BRCA1 engages its binding partner, the BRCA1-associated Ring Domain protein (BARD1) under oxidative stress conditions. We also show how physical differences between wild type and mutated BRCA15382insC impact the cell’s response to oxidative damage. Overall, we demonstrate how clinically relevant changes to BRCA1 affect its structure-function relationship in hereditary breast cancer.
- A rapid and high content assay that measures cyto-ID-stained autophagic compartments and estimates autophagy flux with potential clinical applicationsGuo, Sujuan; Liang, Yanping; Murphy, Susan F.; Huang, Angela; Shen, Haihong; Kelly, Deborah F.; Sobrado, Pablo; Sheng, Zhi (Taylor & Francis, 2015-03-01)The lack of a rapid and quantitative autophagy assay has substantially hindered the development and implementation of autophagy-targeting therapies for a variety of human diseases. To address this critical issue, we developed a novel autophagy assay using the newly developed Cyto-ID fluorescence dye. We first verified that the Cyto-ID dye specifically labels autophagic compartments with minimal staining of lysosomes and endosomes. We then developed a new Cyto-ID fluorescence spectrophotometric assay that makes it possible to estimate autophagy flux based on measurements of the Cyto-ID-stained autophagic compartments. By comparing to traditional autophagy approaches, we found that this assay yielded a more sensitive, yet less variable, quantification of the stained autophagic compartments and the estimate of autophagy flux. Furthermore, we tested the potential application of this autophagy assay in high throughput research by integrating it into an RNA interference (RNAi) screen and a small molecule screen. The RNAi screen revealed WNK2 and MAP3K6 as autophagy-modulating genes, both of which inhibited the MTOR pathway. Similarly, the small molecule screen identified sanguinarine and actinomycin D as potent autophagy inducers in leukemic cells. Moreover, we successfully detected autophagy responses to kinase inhibitors and chloroquine in normal or leukemic mice using this assay. Collectively, this new Cyto-ID fluorescence spectrophotometric assay provides a rapid, reliable quantification of autophagic compartments and estimation of autophagy flux with potential applications in developing autophagy-related therapies and as a test to monitor autophagy responses in patients being treated with autophagy-modulating drugs.
- Structural analysis of BRCA1 reveals modification hotspotLiang, Yanping; Dearnaley, William J.; Varano, A. Cameron; Winton, Carly E.; Gilmore, Brian L.; Alden, Nick A.; Sheng, Zhi; Kelly, Deborah F. (American Association for the Advancement of Science, 2017-09-01)
- Survival kinase genes present prognostic significance in glioblastomaVarghese, Robin T.; Liang, Yanping; Guan, Ting; Franck, Christopher T.; Kelly, Deborah F.; Sheng, Zhi (Impact Journals, 2016-04-12)Cancer biomarkers with a strong predictive power for diagnosis/prognosis and a potential to be therapeutic targets have not yet been fully established. Here we employed a loss-of-function screen in glioblastoma (GBM), an infiltrative brain tumor with a dismal prognosis, and identified 20 survival kinase genes (SKGs). Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that the expression of CDCP1, CDKL5, CSNK1E, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 stratified GBM prognosis with or without temozolomide (TMZ) treatment as a covariate. For the first time, we found that GBM patients with a high level of NEK9 and PIK3CB had a greater chance of having recurrent tumors. The expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary GBM tumors was associated with recurrence-related prognosis. Notably, the level of PIK3CB in recurrent tumors was much higher than that in newly diagnosed ones. Congruent with these results, genes in the PI3K/AKT pathway showed a significantly strong correlation with recurrence rate, further highlighting the pivotal role of PIK3CB in the disease progression. Importantly, 17 SKGs together presented a novel GBM prognostic signature. SKGs identified herein are associated with recurrence rate and present prognostic significance in GBM, thereby becoming attractive therapeutic targets.